Identification of drug-specific public TCR driving severe cutaneous adverse reactions

Abstract

Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.

Immune dysregulation increases the incidence of delayed‐type drug hypersensitivity reactions

“…Furthermore, carbamazepine‐specific cytotoxic T cells could be primed from PBMC of healthy human donors that were carriers of both HLA‐B*15:02 and VB‐11‐IsGSY. More recently, the same group working on the same patient cohort reported the detection of a public T‐cell receptor composed of paired TCRα CDR3 “VFDNTDKLI” and TCRβ CDR3 “ASSLAGELF” clonotypes and that similar receptor clusters are found in the blister fluid cells and peripheral blood . These data suggest that the correct combination of HLA, drug‐peptide complex and T‐cell receptor may be important drivers for carbamazepine‐induced Stevens‐Johnson syndrome.…”

SJS/TEN 2019: From science to translation

“…Multiple predictive genomic markers (Table 2) are subsequently determined to prevent drugspecific SJS/TEN and serum biomarkers such as IL-15 and granulysin [34,35] may have roles in predicting the prognosis of acute stage SJS/TEN. Single-cell (sc) T-cell receptor (TCR) sequencing and repertoire analysis are novel approaches to investigate drug-specific T cell populations and can be paired with sc-RNAseq and Cite-seq to examine expression of the related transcriptome and proteome of total cell populations on interest [48][49]. Dominant TCRαβ clonotypes have been identified in single cells sorted from blister samples of patients with HLA-B*58:01 restricted allopurinol-SJS/TEN and HLA-B*15:02 restricted carbamazepine-SJS/TEN which in the case of the latter represent a public TCRαβ clonotype that is shared amongst unrelated HLA-B*15:02 positive patients with carbamazepine SJS/TEN [48][49].…”

Clinical and pathogenic aspects of the severe cutaneous adverse reaction epidermal necrolysis (EN)

“…Intracellular processing was not required for cytotoxicity 112 . Computational modelling confirmed binding of carbamazepine in the HLA binding groove and interaction with the TCR to establish the TCR‐HLA complex 112–114 . Carbamazepine did not alter the peptide repertoire of HLA‐B*15:2, excluding the altered peptide model of EN pathogenesis 115 …”

“…Apart from the HLA molecules, a specific TCR and peptide presented are required to establish the TCR‐HLA interaction 119–121 . Recently, a preferential TCR clonotype was identified, binding to carbamazepine which can subsequently constitute the interaction between this TCR and HLA‐B*15:2 114 . Regarding the sequence and quantity of the peptide presented by the HLA, variants in genes related to proteasomal function or peptide generation can contribute to the risk for EN 120,122,123 .…”